Maternal obesity increases the risk for offspring to become obese, and there is substantial evidence to suggest that programming during both fetal and neonatal development contributes to this predisposition. Breastfeeding, the recognized gold standard for human neonatal nutrition, is associated with reduced childhood obesity risk. However, emerging evidence from human and animal studies suggests that maternal obesity may override the benefits of breastfeeding on the metabolic health and obesity risk of nursing offspring. Our study is directed at understanding the mechanisms by which maternal obesity influences the metabolic predisposition of their off-spring to obesity. We established a mouse model that allows us to define postnatal contributions of maternal obesity to neonatal metabolic health and obesity predisposition, distinguishing the specific effects of maternal obesity from those imparted by maternal consumption of a high fat (HF) obesigenic diet. Our data document that milk from obese dams selectively programs obesigenic changes in neonatal metabolism. In recent work we linked these changes to impaired de novo milk lipid synthesis due to inhibition of acetyl- CoA carboxylase-1 (ACC1), and the production of lipid-poor milk by obese dams. The overall goals of this proposal are to use obese mouse models in conjunction with innovative genetic manipulation and quantitative metabolic and imaging approaches to: (1) define the effects of maternal obesity on off-spring obesity predisposition; (2) detail the effects of milk frm obese dams on neonatal metabolism; (3) define the roles ACC1 and de novo lipogenesis in the obesity-associated alterations in milk that promote neonatal obesity. The detailed systematic investigation of the physiological and molecular mechanisms underlying postnatal effects of maternal obesity on neonatal metabolic health, as outlined in this proposal, form the foundation for development of new intervention strategies to prevent obesity.